Abstract 17076: Attenuating Endoplasmic Reticulum (ER) Stress as a Novel Therapeutic Strategy in Pulmonary Arterial Hypertension
The poor prognosis associated with pulmonary arterial hypertension (PAH) is in part, due to the complex and poorly understood pathogenesis. ER stress is a potential common denominator among many of the seemingly unrelated molecular triggers of PAH, including BMPRII mutations and the misfolded protein response that follows, viruses, inflammation, Notch signaling and hypoxia. The ER forms a functional unit with the mitochondria (the ER-mito unit), allowing exchange of Ca2+, lipids and ATP between the organelles. Recently, we showed that disruption of the ER-mito unit was critical in PAH pathogenesis. ER stress-regulated induction of the reticulon protein Nogo caused structural/functional disruption of the ER-mito unit resulting in PAH. Chemical chaperones including the clinically studied 4-phenylbutyrate (PBA) can attenuate ER-stress and have been used in animals and patients to treat metabolic diseases and cancer. We hypothesized that attenuation of ER stress with PBA will prevent the disruption of the ER-mito unit and prevent/reverse PAH. We used two models of PAH associated with ER stress: hypoxia and monocrotaline (MCT). Mice exposed to chronic hypoxia and treated with PBA in the drinking water (~750mg/kg/day) in both prevention and reversal protocols had less distal pulmonary artery remodeling, improved hemodynamics, decreased right ventricular hypertrophy and better functional capacity (see table; data presented as mean±SEM). MCT-animals responded similarly. Mechanistic studies were performed in human cell lines and tissues from these animals. We showed that 2mM PBA decreased ER stress (decrease in the marker grp78), decreased Nogo and normalized the ER-mito unit (mitochondrial calcium and membrane potential). Both in vivo and in vitro, PBA suppressed proliferation (Ki67/PCNA) and induced apoptosis (TUNEL) in SMA+ cells. Metabolism and ER stress may be a common downstream effect of many diverse triggers of PAH and may expose a new therapeutic window.
- © 2011 by American Heart Association, Inc.